Binding of nerve growth factor (NGF) to the low affinity neurotrophin receptor, p75/NTR, induces the hydrolysis of sphingomyelin (SM) and generation of the pro-apoptotic lipid metabolite, ceramide. However, a significant gap exists in our understanding of how this p75/NTR- dependent signaling pathway is organized is organized and regulated. The long range goal of this research is to develop a more comprehensive understanding of the molecular mechanisms of P75/NTR-dependent signaling. The rationale for investigating the mechanisms of P75/NTR signaling is underscored by the emerging role of p75/NTR-dependent ceramide production in mediating neuronal apoptosis. Evidence has been obtained that the p75/NTR-SM signaling pathway is organized in caveolae, invaginations of the plasma membrane enriched in SM and other signaling molecules. Significantly, despite the presence of p75/NTR in non- caveolar regions of the membrane, only the caveolar pool of p75/NTR is involved in hydrolyzing SM and generating ceramide via the activation of an acid sphingomyelinase (SMase). Further, p75/NTR specifically associates with caveolin, the main protein constituent of caveolae which serves to organize and sequester signaling molecules within caveolae. The central hypothesis to be tested is that specific factors regulate the interaction of p75/NTR-dependent activation of an acid SMase. The specific aims of this project are: 1) to determine how p75/NTR interacts with structural proteins of caveolae; and 2) to identify the mechanism of p75/NTR-dependent activation of acid sphingomyelinase in caveolae. The expected outcome of these studies is that we will provide important and novel information relevant to our understanding of signal transduction pathways operative in neurodegenerative processes.